Effectiveness and Cost-Effectiveness of Echocardiography and Carotid Imaging in Management of Stroke

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Summary (continued)

Carotid Imaging

The role of carotid imaging is better established than that of echocardiography in patients with stroke. It is clear that carotid artery stenosis conveys increased risk of stroke and that efficacious treatment exists to reduce that risk. However, the most effective imaging strategy for diagnosing carotid artery stenosis is controversial. The most widely used tests include two noninvasive tests, carotid ultrasound and magnetic resonance angiography, and one invasive test, cerebral angiography. These tests may be used alone or in various combinations. Although the noninvasive tests are not associated with significant complications, their effectiveness in predicting who will benefit from surgical intervention has not been directly established, as it has for angiography. The noninvasive tests therefore carry the potential for false positive and false negative diagnoses and the consequent risk of selecting patients without significant carotid stenosis for ineffective and potentially harmful surgery, or excluding patients with significant stenosis from beneficial treatment. In order to compare the effectiveness of various strategies for carotid imaging, evidence related to the following was examined:

Key Question 1. What are the operating characteristics of available tests for measuring carotid artery stenosis?

Despite numerous studies of the accuracy of noninvasive carotid imaging, relatively few have been conducted in which all patients undergoing noninvasive tests also undergo diagnostic confirmation with cerebral angiography. The lack of diagnostic verification in these studies creates biased estimates of sensitivity and specificity. Studies can adjust for this bias by angiographically studying a random sample of subjects with negative noninvasive tests. Studies were reviewed of CUS and MRA accuracy that either had no obvious or likely verification bias or that adjusted for this bias.

It is clear from the literature that the accuracy of CUS in diagnosing carotid stenosis varies substantially across centers. It is likely that published reports of the accuracy of CUS from single centers overestimate the accuracy in most settings. This has two important implications. First, it may be inappropriate for individual practitioners or medical centers to assume that the accuracy of CUS in their practices is equivalent to published figures. Second, it is clear that there is potential for CUS to be highly accurate. The sensitivity and specificity of CUS estimated from SROC curves constructed from the results of eight predominantly fair-quality studies were 80 and 91 percent, respectively, for moderate or greater (> 50 percent) stenosis, and 75 and 87 percent for severe (> 70 percent) stenosis. When the largest and only good-quality study was excluded, sensitivity and specificity for severe stenosis rose to 94 and 84 percent. The lower accuracy in the largest study than in other studies may have been due to the use of conventional rather than color-flow duplex imaging, but may also have been due to the representation of multiple centers. Reports from single centers may provide biased estimates of accuracy, as those centers finding low accuracy may choose not to submit their results for publication.

Whether the accuracy of MRA varies by center is not clear. There have not been multicenter studies of MRA. Published data, excluding studies with obvious or likely verification bias, suggest a sensitivity and specificity of 92 and 97 percent for detecting severe stenosis. However, studies of MRA were generally of fair to poor quality. As with CUS, it is possible that centers publishing their accuracy data are not representative of all users of MRA. Until there are more high-quality data on the accuracy of MRA, current estimates of MRA accuracy in measuring carotid stenosis must be interpreted cautiously.

All studies of the accuracy of CUS and MRA used in combination were biased by incomplete verification. In the majority of these studies, sensitivity was 100 percent. However, the studies were generally of poor quality. The specificity of combined CUS and MRA was variable, ranging from 69 to 100 percent. The estimated sensitivity and specificity of combined CUS and MRA for detecting severe stenosis were 95 and 98 percent, respectively. In approximately 18 percent of patients, the results of CUS and MRA in detecting severe stenosis were discordant.

Key Question 2. What is the incidence of complications associated with cerebral angiography?

In prospective studies examining the incidence of stroke and death following cerebral angiography in patients suspected of having cerebrovascular disease and potential candidates for CEA, the overall rate of 0.02 percent for deaths was lower than the 0.08 percent rate previously reported. Only two deaths were found in 10 studies including 3,074 patients.

Significant heterogeneity was found between rates of combined stroke or death from all studies as well as between studies stratified by various methodologic criteria. The rate of combined stroke or death ranged from 0 percent to 4 percent in three studies rated as having good quality, with the study rated as having the highest quality reporting a rate of 1.3 percent (95 percent CI, 0.5 to 2.8 percent).

The risk of complications appears higher in patients with greater degrees of carotid stenosis, who are also those patients most likely to benefit from subsequent CEA.

The magnitude of incremental risk of cerebral angiography (i.e., the risk above the baseline risk of recurrent stroke or death in recently symptomatic patients) cannot be reliably estimated at this time but would be expected to be lower than the rates reported above.

Key Question 3. What is the efficacy of carotid endarterectomy in reducing the rate of recurrent stroke among symptomatic patients with carotid artery stenosis?

In two large, good-quality randomized controlled trials (RCTs), carotid endarterectomy reduced the risk of disabling stroke or death for surgically fit patients with symptomatic ipsilateral stenosis greater than 70 percent as measured by the European Carotid Surgery Trial (ECST) method, and over 50 percent as measured by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. In a meta-analysis of these trials, the number needed to treat to prevent one disabling stroke or death over 2 to 6 years was 15 (95 percent CI, 10 to 31) for severe stenosis (70 to 99 percent by NASCET criteria or 80 to 99 percent by ECST criteria) and 21 (95 percent CI, 11 to 125) for moderate stenosis (50 to 69 percent by NASCET or 70 to 79 percent by ECST). No benefit was seen in patients with lesser degrees of carotid stenosis. In the subgroup of patients with severe stenosis, increased degree of stenosis was associated with greater benefit from surgery. The results of the studies are generalizable to surgeons and centers with low perioperative complication rates (30-day stroke or death rate less than 6 percent). The studies did not include angiographic morbidity or mortality in their results.

Although patients over 80 years old, non-whites, and females were underrepresented in these studies, multivariate analysis to determine factors associated with increased benefit was performed on these and other clinical and demographic characteristics in the two trials. In NASCET and ECST, less benefit was seen in females for all degrees of carotid stenosis, and among patients with 50 to 69 percent stenosis, the absolute risk reduction was eight-fold lower in women than in men. The lesser degree of benefit for women may be partially due to a lower baseline recurrent stroke rate compared to men for equivalent degrees of carotid stenosis. Older age was associated with increased benefit in ECST and in the subgroup of patients in NASCET with 70 to 99 percent stenosis.

It must be noted that among patients screened in the NASCET, fewer than one-third were randomized. Approximately one-third did not fulfill baseline criteria, 15 percent were excluded for medical reasons, and another 23 percent were eligible but not randomized. Such exclusions must be considered when trying to generalize data from the endarterectomy trials to individual patients or populations of patients in "real-world" health care settings.

Key Question 4. What is the incidence of complications associated with carotid endarterectomy?

Using data from 12 studies of good quality, the pooled rate of combined perioperative (30-day) stroke or death associated with CEA was 6.8 percent (95 percent CI, 4.6 to 9.5 percent), and from nine studies of good quality, the pooled rate of death alone was 1.6 percent (95 percent confidence interval, 1.0 to 2.5 percent).

In NASCET, the 30-day postrandomization rate of stroke or death ranged from 2.4 percent (for patients with < 70 percent carotid stenosis) to 3.3 percent (70 to 99 percent stenosis) in patients assigned to medical therapy. Therefore, surgery is associated with an additional 35 to 44 perioperative events per 1,000 patients. In NASCET, approximately 60 percent of the strokes that occurred in the perioperative period were nondisabling (Rankin score < 3).

Methodologic characteristics of the studies explained some of the variation in complication rates. Population-based studies, RCTs, studies with independent ascertainment of complications, studies with nonsurgeon authors, and studies published since 1990 were associated with higher combined complication rates. The pooled complication rate in randomized controlled trials was higher than the pooled rate for other studies, suggesting that these trials may have high generalizability despite strict selection criteria. Population-based studies also reported relatively high perioperative complication rates. All of the characteristics associated with higher complication rates appear to occur in studies rated as having higher average methodologic quality.

The appropriate timing of carotid imaging depends partly on the timing of CEA. CEA is often delayed for several weeks after stroke onset due to concerns about the safety of CEA in the acute period. There is fair evidence that early as compared with delayed CEA is not associated with an increased risk of major complications. Three nonrandomized studies of fair quality suggest that in patients with recent minor or nondisabling stroke, CEA performed earlier than the traditional waiting period of 4 to 6 weeks is not associated with significantly increased adverse events compared to delayed surgery, with a pooled rate of 3.3 percent for early CEA versus 5.3 percent for later CEA. When data from all studies (including seven rated poor quality) are included, the pooled rate of major perioperative complications (stroke or death) is 3.9 percent for early CEA versus 2.7 percent for later CEA. The pooled rate of death alone from all studies was about 1.0 percent in patients undergoing either early or later CEA. There was a nonsignificant trend toward better outcomes for early CEA in studies published since 1990.

There is insufficient evidence to draw conclusions regarding the risk of very early CEA (i.e., less than 1 week after presenting with symptoms). There is also inadequate evidence to draw conclusions for specific subgroups, including patients with specific computed tomography scan findings and greater degrees of carotid stenosis. Patients selected for early CEA in these studies are likely to comprise an overall lower-risk population compared to patients not selected for early CEA, though in higher-quality studies patients undergoing early and later CEA were comparable according to important clinical and demographic criteria.

Cost-Effectiveness: What strategies for using carotid imaging are cost-effective? The lack of good or consistent evidence regarding the accuracy of noninvasive carotid imaging strategies makes it difficult to accurately determine the most cost-effective strategy for selecting patients with stroke for CEA. Assuming the accuracy of statistics derived from this review, two testing strategies provide the most benefit when compared to no testing: first, administer MRA and refer patients with severe (70-99 percent) stenosis directly to CEA. Second, administer joint CUS and MRA, and when both tests demonstrate moderate to severe (50-99 percent) stenosis, refer patients directly to CEA. When the two tests disagree, request angiographic confirmation. The incremental cost-effectiveness ratios for these two strategies are approximately $250,000 and $700,000 per QALY, respectively.

In sensitivity analyses, the variable with the greatest influence on the results of the carotid imaging model was the prevalence of severe carotid stenosis. At severe stenosis prevalences of 0.15 and below, all testing strategies were dominated by the strategy of no testing or had cost-effectiveness ratios exceeding $250,000 per QALY (0.15 was the prevalence assumed in the base-case analysis). However, as this prevalence increased above 0.15, the cost-effectiveness ratios of two strategies, CUS with angiographic confirmation of severe stenosis (CUS/Angio-70), and MRA with direct CEA referral for severe stenosis (MRA/70 percent), fell precipitously, such that at a prevalence of 0.20, these strategies had cost-effectiveness ratios in the range of $60,000 to $75,000 per QALY. At higher prevalences, these ratios fell further. When compared to the strategy of no testing, CUS/Angio-70 had an incremental cost-effectiveness ratio of less than $50,000 per QALY at a prevalence of 0.25, while the incremental cost-effectiveness of MRA/70 fell below $50,000 per QALY as the prevalence of severe stenosis approached 0.30.

These results suggest that carotid imaging may compare unfavorably, in terms of cost-effectiveness, with other commonly endorsed health care interventions, when the prevalence of carotid stenosis is low. Carotid imaging may be most efficient for those with a high pretest probability of severe stenosis, e.g., patients with peripheral vascular disease or audible carotid bruits.

Varying the cost of testing did not substantively affect the results, except in the case where MRA was assumed to cost $2,500 (as opposed to $1,249 in the base-case analysis). In this analysis, the strategy of initial CUS with angiographic confirmation of severe stenosis became undominated, with a cost-effectiveness ratio of $280,000 per QALY. Varying the accuracy of the different testing strategies over wide ranges did not have a substantial overall effect on the results. When the perioperative complication rate was assumed to be zero, noninvasive strategies involving direct referral to CEA of patients with moderate or greater stenosis expectedly became the most cost-effective; without risk of complications, angiographic confirmation to avoid false positives was no longer beneficial, and the marginal benefit of CEA among patients with moderate stenosis was no longer counterbalanced by perioperative risk. Varying the duration of risk reduction associated with CEA between 2 and 10 years also did not substantively affect the cost-effectiveness ratios. Likewise, restricting the cohort to only patients with TIA or minor stroke, which reflects the patient populations in the two large carotid endarterectomy trials, did not have a major impact on cost-effectiveness ratios, though it did produce a different set of undominated strategies.

It is noteworthy that strategies in which patients with moderate (50-69 percent) stenosis were referred for CEA provided fewer QALYs than strategies in which such patients were treated nonsurgically, despite the fact that the review (and hence the model inputs) reflected an overall benefit from CEA for moderate stenosis. This occurred as a result of the fact that the benefit of CEA over nonsurgical management in patients with moderate stenosis is small, such that when a 3 percent discount rate is applied to account for the fact that health benefits incurred or realized in the future are considered to be of lower value than benefits realized in the present, the future benefits are outweighed by the perioperative complications incurred immediately after surgery. When perioperative complication rates were assumed to be zero, or when the discount rate was removed, strategies involving CEA for patients with moderate stenosis became more cost-effective.

Future Research

In the course of the review, several information gaps related to the effectiveness of echocardiography in the management of patients with stroke emerged. Most notable are the gaps in knowledge about the presence and degree of risk of stroke conveyed by echocardiographically identified lesions, and the efficacy of therapy in reducing that risk. Identifying the risk of recurrent stroke associated with echocardiographic lesions can be achieved through cohort studies of patients with and without these lesions, while the efficacy of treatment is best addressed through RCTs. Because RCTs can address recurrent stroke risk and treatment efficacy simultaneously, this study design would provide valuable information needed to establish the usefulness of echocardiography in stroke. Trials of anticoagulation for complex aortic atheroma and ASA (with and without PFO), lesions for which available evidence suggests an association with stroke and which are observed relatively frequently, may be the most appropriate for initial study. Some of these studies are already ongoing.

Additional studies that would help solidify the evidence related to echocardiography in stroke involve the accuracy and yield of echocardiography. Most studies of the accuracy of TTE in detecting LVT were conducted in the early 1980s, when echocardiography was still a relatively new technology. Newer studies assessing the accuracy of TTE in diagnosing LVT as verified surgically or pathologically would provide helpful data for calculations of the effectiveness and cost-effectiveness of TTE in stroke patients. In addition, interobserver reliability should be assessed in these studies.

Further studies examining the yield of echocardiographic lesions on TTE and TEE would also add valuable information. Such studies would be most useful if consecutive stroke patients without AF were prospectively enrolled; if results were stratified by age, presence or absence of carotid artery stenosis, presence or absence of manifest cardiac disease, and stroke subtype and location; and if studies were conducted in community-based settings, preferably across multiple centers. This type of study would require collaboration across institutions, but data collection may be facilitated by the presence in some centers of stroke registries and registries of patients undergoing echocardiography.

Finally, studies establishing the complication rates of TEE in patients with stroke are needed. Because patients with stroke often have swallowing difficulties as well as coexisting heart disease, TEE-associated complications may occur more frequently in patients with stroke than in other patients. The harms associated with TEE must be accurately quantified in order to assess its overall utility.

Future economic evaluations would benefit from more accurate estimates of the cost of both TTE and TEE. While charges for these two tests, as assessed by Medicare, are similar, the actual cost of TEE may be substantially higher than that of TTE, due to the cost of additional time, equipment, and personnel required for TEE. Microcosting studies may help clarify the cost of these additional expenditures.

While additional research on diagnostic accuracy, including studies that either eliminate or adjust for verification bias, may help to clarify the accuracy of CUS, the finding that accuracy may vary from center to center suggests that it may not be possible to establish a generalizable estimate of CUS sensitivity and specificity. It may be more fruitful to conduct studies examining the factors (e.g., technical experience, quality management programs) that allow some centers to achieve higher CUS accuracy than others.

High-quality studies of MRA accuracy and reliability, particularly for contrast-enhanced MRA, both alone and in combination with CUS, are needed. Such studies should prospectively image consecutive patients with stroke and angiographically verify the presence or absence of stenosis in all patients; if this is not possible, a random sample of patients with negative MRA should undergo angiography for the purpose of adjusting for verification bias. Multicenter studies would be helpful in limiting the potential influence of publication bias and in clarifying the variability of accuracy across centers.

Studies of CEA complications indicate that complication rates are highly variable. Collaborative studies assessing the sources of this variability and potential interventions to reduce it, as has been done for coronary artery bypass graft surgery, may improve the quality of operative care and thereby improve the effectiveness of all strategies for carotid imaging.

Trials assessing the efficacy and safety of early versus late CEA would help in determining the most appropriate timing of carotid imaging. If early CEA (e.g., within 1 week of initial symptoms) were found to be as safe as delayed CEA, early recurrent strokes (within 30 days of symptom onset) might be avoided, thereby increasing the efficacy of CEA. If this were the case, the effectiveness of carotid imaging might be maximized when done shortly after initial presentation.

In addition to these recommended clinical studies, future economic evaluations of carotid imaging strategies would benefit from comparisons of the outcomes of CEA with those of the latest nonsurgical treatments for carotid stenosis. This would inform the issue of the appropriate comparator to CEA. Furthermore, economic evaluations would benefit from improved data on the epidemiology of recurrent stroke, the prevalence of moderate and severe carotid stenosis, and the relative benefits of CEA versus non-surgical management across clinical and demographic patient subgroups. Finally, new studies are needed of the costs and benefits of carotid imaging strategies beyond their use in decisionmaking about CEA, e.g., the potential value of information from carotid imaging in the diagnosis and treatment of cardiac disease.

Availability of Full Report

The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality by the Oregon Evidence-based Practice Center under contract No. 290-97-0018. Print copies of this report are available free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment No. 49, Effectiveness and Cost-Effectiveness of Echocardiography and Carotid Imaging in the Management of Stroke (AHRQ Publication No. 02-E022).